This invention relates generally to an article of manufacture for the photodynamic therapy (PDT) of dermal lesion such as for example actinic keratosis, basal carcinoma and psoriasis. More particularly, this invention relates to an article of manufacture for applying photodynamic therapy to a dermal lesion and which article of manufacture includes a transparent transport system containing hydration agent and photopharmaceutical and light delivery means for photoactivating the photopharmaceutical; the hydration agent hydrates primarily the corneum stratum of the epidermis to render the corneum stratum more transparent to the passage of light and the photopharmaceutical therethrough.
Bodies, sheet or layer forms, of hydrogel or hydrogel materials, particularly transparent (to light) hydrogels or hydrogel materials, are well known in the medical field and may comprise, for example, a polyvinyl alcohol with a water matrix; some of these transparent hydrogels are castable gels or materials. They have been widely adapted to such applications as diagnostic electrodes (for EKG), wound care dressings, and transdermal delivery devices for systemic delivery of pharmaceutical agents. The biocompatability of this class of materials is well established for extended contact with dermal structures. Much of the prior art in medical applications for hydrogel or hydrogel materials teaches devices and methods for electrical conductivity enhancement. Critical in using hydrogel in many medical applications, such as an electrical interface, is the ability of the hydrogel to form intimate physical contact with skin or dermal structures. U.S. Pat. 5,143,071 issued to Keusch et al. on Sep. 1, 1992, cites an extensive list and description of prior art hydrogels suitable for this purpose, and this patent is incorporated herein by reference.
A concurrent body of prior art embraces hydrogels or hydrocolloids, as wound dressings and dressings impregnated with pharmaceutical compounds; representative of this prior art is U.S. Pat. 5,156,601 to Lorenze et al. Further, the work of Gombotz et al., Proc. Intl. Symp. Cont. Rel. Bioact. Mtl., Vol. 19, 1992, describes the rapid release of complex compounds from hydrogels to skin or dermal structures.
U.S. Pat. No. 5,079,262 issued to Kennedy et al. discloses a method of detection and treatment of malignant and non-malignant lesions utilizing 5-aminolevulinic acid. The acid is administered to a patient in an amount sufficient to induce synthesis of protoporphyrin IX in the lesions, followed by exposure of the treated lesions to a photoactivating light in the range 350-640 nm. The acid is administered to the patient orally, topically or by injection, but not through a hydrogel coupling; this patent is incorporated herein by reference.
None of the prior art references teach or suggest the photodynamic therapy of dermal lesions using transparent hydrogel as a coupling agent for light and photopharmaceutical. Since its first reported clinical use at the turn of the century, photodynamic therapy has been accomplished using light projected to the dermal treatment site from sources at some distance from the site. Modern photodynamic therapy (from 1978 onwards) has developed light delivery protocols using artificial sources such as tungsten halogen, or xenon arc lamps with wavelength filtration to activate photopharmaceuticals. All of the above light sources have been used in projective, field illuminating devices that flood the target treatment field or site in the treatment of superficial cutaneous lesions with light containing a wavelength designed to activate the photopharmaceutical.
In the case of the tungsten and xenon-arc sources, extensive filtration of the available light flux is essential to restrict the delivered energy to appropriate wavelengths that photoactivate the photopharmaceutical in the target dermal structures. Colored glass or interference filters used with these sources transmit some portion of unwanted wavelengths, notably in the infrared region, and can cause thermal effects that may mask the effect of photoactivity with an undesirable heating effect that also preferentially damages malignant tissue. High-power surgical lasers, even when de-focussed, also can induce undesirable thermal effects. The work of Svaasland, Photochem/Photobiol. 1985, measured this effect and its impact on PDT protocols.
Dosmerry of delivered photodynamically effective light to a dermal treatment site is extremely difficult using current projective optics. Mathematical modeling of skin optics has been a slow and difficult process. Recent publications by Van Gemert et al., IEEE Trans. Biomed. Eng., Vol. 36;12, 1989, critically reviewed the prior work and presents a 4-layer model of light-dermal tissue interaction; this publication is incorporated herein by reference Van Gemert et al. elaborates on the advantages and effectiveness of the diffusion model of light transport in tissue, which depends upon the efficient coupling of the externally applied light to the target tissue. A later publication by R. Rox Anderson, Optics of the Skin, Clinical Photomedicine, Dekker Publication, 1993, reviews the two basic processes which govern the optics or behavior of light in skin, namely, light absorption and light scattering; this publication is incorporated herein by reference.
It has been found that an efficient and practical means of establishing the diffusion conditions of light transport is to provide a transparent coupling means that is in intimate contact with the dermal lesions on one surface and with the light source on its opposite surface. Under these conditions reflective losses are reduced, and delivered energy is much more efficiently transmitted into the target region.
The stratum corneum present at a dermal treatment site on the skin of a person is a formidable barrier to transport (transmission, penetrability or permeability) of light into the deeper structures of the skin where dermal lesions typically reside, in whole or in part. The layered plate-light corneocytes comprising the stratum corneum constitute an efficient reflective optical surface which reflects nearly all light in the visible spectrum. There is some transmission in the region of 590 to 700 nanometers. Photopharmaceuticals are formulated to be activated by light energy in this region. Penetration depth is in the region of 1-3 mm from the dry corneocyte surface. It has been discovered that the interposition of a flexible transparent hydrogel coupling layer between a monochromatic plate or sheet-formed light source and the skin surface constitutes a new and more efficient delivery of activating optical energy to target dermal lesions for photodynamic therapy; particularly where the monochromatic light source delivers light at the specific wavelength at which the photopharmaceutical is photoactivated.
There are other substantial benefits that attend the use of an intimately contactive hydrogel coupling layer. Because hydrogels are typically 60 to 90% water, hydration of the stratum corneum occurs rapidly following contact with the hydrogel sheet. This hydration has a substantial optical transparency, or optical transmissiveness, enhancing effect, allowing more light to pass through the stratum corneum. Although the mechanism of this optical transparency has not been extensively studied, it is thought to result from a reduction of the light reflectivity of the stratum corneum through softening of the corneocytes by a solvent or plasticizing action.
It is well established in the literature of chemical transport through the skin that hydration can enhance the chemical transparency, transmissiveness, passage or transport of pharmaceuticals through the stratum corneum. A review and discussion of this enhanced transport under hydrated conditions is found in Ghosh et al., Pharmaceutical Tech., Apr. 1993, which publication is incorporated herein by reference.
It follows that there are two key requirements of PDT to dermal structures where the protocol requires topical application of the photopharmaceutical. Transport of the photopharmaceutical into target tissue, and subsequent light activation of the photopharmaceutical at the target tissue, these can be more efficiently accomplished using the diffusion route for both the drug and the activation optical energy.
It has been found that a transparent hydrogel coupling layer serves the dual purpose of establishing conditions for the optical energy diffusion into skin tissue and photopharmaceutical compound diffusion or other introduction into skin tissue, by the intercellular or transcellular routes; however, it will be understood that the introduction of the photopharmaceutical from the hydrogel into the hydrated skin or through the hydrated stratum corneum, depending on the specific photopharmaceutical used, can be by the above-noted diffusion, or by absorption, or by other mechanism constituting chemical permeation or penetration of the hydrated skin or stratum corneum. A third optical advantage of a transparent transport hydrogel is that it can remain in place after PDT exposure, as a protective dressing.
It is an object of this invention to provide an article of manufacture for the combined delivery of a photopharmaceutical and light for photodynamic therapy of dermal lesions utilizing a transparent carrier, reservoir or transport of hydration agent and photopharmaceutical, and which transparent transport acts as an efficient coupler between a light source and dermal surface.
In the preferred embodiment of this invention, a transparent hydrogel serves as a transport or reservoir of a hydration agent and photopharmaceutical and which hydrogel rapidly releases the photopharmaceutical to the skin tissue. For purposes of photodynamic therapy, rapid delivery is desirable. This contrasts with prior art transdermal devices for non-PDT drug delivery which seek to provide much slower release kinetics for system absorption. Further, in the present invention, the photodynamic therapy is localized to a dermal treatment site defined by a cover, container or patch covering the site where the dermal lesion is located and the light necessary to activate the photopharmaceutical is delivered only to the dermal treatment site. It is thus advantageous to rapidly deliver the light activated photopharmaceutical doses to skin tissue, and dermal lesion, and then deliver the light dose to initiate its biological activity to treat the dermal lesion.
The intimate transparent hydrogel contact established at the skin surface of the treatment site forms both a fluid or fluidic coupling for the photopharmaceutical and an optical or optic coupling for the photoactivating light. In the case of the fluidic coupling, the water contained in the hydrogel matrix begins to solubilize the stratum corneum, hydrating this normally dry layer, and forms an avenue of exchange between the hydrogel and the dermal lesion. Hydration enhances both intracellular and transcellular pathways. Upon establishment of these pathways, transport of the photopharmaceutical to target tissue or dermal lesion commences.
The effect of hydration on fluid transport across the stratum corneum layer is substantial. Normally this structure contains 10-15% water. Hydrated stratum corneum can retain up to 50% water and the normal light diffusion coefficient of the hydrated stratum corneum can increase ten-fold.
The effect of hydration on optical coupling of light into skin tissue is also substantial, but is sustainable only with the contact of the transparent hydrogel to both the skin tissue and the light source. In the preferred embodiment a fiber optic panel comprising a plurality of fiber optic strands is used as a light delivery source to activate the photopharmaceutical, and hydrogel contact with the fiber optic strands is efficient because at manufacture the hydrogel is cast against the fiber optic strands and conforms to the regular geometry of these strands. The formation of the hydrogel to skin surface juncture occurs at the point of engagement of the hydrogel to the skin surface. The physical characteristics of the hydrogel necessary to establish intimate skin contact are those described for electrode contact in the prior art references, cited above. Similar characteristics are required for performing PDT with the present invention, with the added hydrogel attributes of light transmission and hydration of the skin.
The mechanical changes hydration produces in the stratum corneum layer have substantial impact on the optical coupling efficiency of externally applied light in the red region of the spectrum. The ultra-structure of the stratum corneum is an array of flattened essentially dead cells which are constantly being shed in a natural process of skin surface renewal. This results in a very uneven, dry, and highly light reflective layer or barrier to light penetration or transmission. Hydration by contact with emollients and oil-based unguents confers an improved surface but the effect is transitory under projected optical illumination schemes that, through surface heating, rapidly degrade the hydration effect by drying out of the target region. Thus though topically applied agents for PDT may briefly induce an optical improvement, it rarely persists through the projected light illumination phase if surface heating occurs during illumination.
This is in marked contrast with the present invention, where the hydrogel remains in place during the light dosage and serves as a hydration agent and photopharmaceutical reservoir or transport means, and conduit and coupling for both light and fluidized agents to the target tissue or dermal treatment site during all phases of photodynamic therapy of a dermal lesion.